Tri Widiandani (2017) Modifikasi Struktur N-(Alilkarbamotioil)Benzamida Dan Hubungan Kuantitatif Struktur-Aktivitas Sitotoksiknya Pada Sel Kanker Payudara Mcf-7/Her-2. Disertasi thesis, UNIVERSITAS AIRLANGGA,.

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Abstract

Breast cancer with HER-2 overexpression is sensitive to drug targeting the receptor or its kinase activity, although anti-HER-2 therapies have improved patient outcome, but resistance ultimately occurs. In this present study, we investigated a modification of the chemical structure of allylthiourea in order to enhance the cytotoxicity effect on human breast cancer cell lines and its protein expression in HER-2. The aims of this study are to modify allylthiourea and evaluate their activity by using in silico and in vitro method. The thirteen (13) compounds: N- (allylcarbamothioyl)benzamide; N-(allylcarbamothioyl)-4-chlorobenzamide; N- (allylcarbamothioyl)-3-chlorobenzamide; N-(allylcarbamothioyl)-2-chlorobenzamide; N-(allylcarbamothioyl)-3,4-dichlorobenzamide; N-(allylcarbamothioyl)-2,4-dichloro benzamide; N-(allylcarbamothioyl)-4-bromobenzamide N-(allylcarbamothioyl)-4- fluorobenzamide N-(allylcarbamothioyl)-4-methylbenzamide; N-(allylcarbamothioyl)-4- methoxybenzamide; N-(allylcarbamothioyl)-4-tert-buthylbenzamide; N- (allylcarbamothioyl)-4-nitrobenzamide; N-(allylcarbamothioyl)-trifluoromethyl benzamide were synthesized by Schotten-Baumann reaction with benzoyl chloride derivatives. The structures of the compounds were confirmed by using IR, 1H-NMR, 13CNMR and MS spectroscopic methods. The virtual screening was carried out through docking of the compounds into the binding site of human growth factor receptor (HER-2), with PBD code: 3PP0 to predict their’s activity as anticancer. In silico study was performed by using MVD ver. 5.5. All the synthesized compounds have a smaller Rerank Score than lead compound and also a commercially available anticancer drug, hydroxyurea. The small RS value implied a molecular bond that was stable and predicted had high biological activity. Biological evaluations were conducted on MCF-7 and MCF-7 cells with overexpressing HER-2 is using MTT assay and western blot. The result showed the BATU performed cytotoxicity effects on MCF-7/HER-2 cell line higher than on MCF-7 cell lines. In addition, all derivatives also performed cytotoxicity effects on MCF-7 and MCF-7/HER-2 higher than allylthiourea as a lead compound. This finding also confirmed that The N-(allylcarbamothioyl)benzamides can effectively enhance the cytotoxicity effect against MCF-7/HER-2 through enhanced HER-2 expression and inhibition of NF- κB activation. Based on the QSAR, it can be concluded that there is a linear relationship between in silico (RS) and in vitro cytotoxic activity against cell line MCF-7/HER-2. And as the best QSAR equation is an equation with three parameters: Log 1/IC50 = -0.096 (Clog P)2 + 0.814 Clog P + 0.014 tPSA - 0.007 Etot - 4.642. From the selected equation can be explained that the effect on the cytotoxic activity of the N-(allylcarbamothioyl)benzamide and its derivatives are lipophilic (Clog P and tPSA) and electronic (Etot) properties.

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